A Novel Enterococcus Phage Endolysin Lys22 with a Wide Host Range Against Mixed Biofilm of Enterococcus faecalis, Staphylococcus aureus, and Acinetobacter baumannii. - Related Documents




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974701.0000A Novel Enterococcus Phage Endolysin Lys22 with a Wide Host Range Against Mixed Biofilm of Enterococcus faecalis, Staphylococcus aureus, and Acinetobacter baumannii. The global surge in multidrug-resistant (MDR) bacterial pathogens has created an urgent imperative for innovative antimicrobial strategies. Enterococcus faecalis, Staphylococcus aureus, and Acinetobacter baumannii demonstrate remarkable antibiotic resistance and dominate hospital-acquired infections. These bacteria often form biofilms, a complex community structure that shields them from immune system phagocytosis, resists antibiotic penetration, and enhances their survival in hostile environments. In clinical cases, these bacteria often form mixed biofilms and lead to treatment failures. Phages and their derivatives have emerged as promising candidates in the fight against drug-resistant bacteria. Lys22, an endolysin derived from an enterococcus phage, has been cloned and demonstrated to possess a broad host range, effectively targeting E. faecalis, various Staphylococcus species, and A. baumannii. When applied to the biofilms formed by these bacteria, Lys22 was found to significantly inhibit both simple and complex biofilms in vitro. Virulent genes, including agrA, sarA, and icaA in S. aureus; asa1, cylA, and gelE in E. faecalis; and OmpA and lpsB in A. baumannii were also downregulated by Lys22. Notably, Lys22 also exhibited a robust protective effect against dual or triple infections involving E. faecalis, S. aureus, and A. baumannii in a zebrafish embryos model, highlighting its potential as a therapeutic agent in combatting multi-bacterial infections.202541156670
884010.9996Role of Biofilm in Bacterial Infection and Antimicrobial Resistance. Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. Microbial flora which produces biofilm manifests an altered growth rate and transcribes genes that provide them resistance to antimicrobial and host immune systems. Biofilms protect the invading bacteria against the immune system of the host via impaired activation of phagocytes and the complement system. Biofilm-producing isolates showed greater multidrug resistance than non-biofilm producers. Biofilm causes antibiotic resistance through processes like chromosomally encoded resistant genes, restriction of antibiotics, reduction of growth rate, and host immunity. Biofilm formation is responsible for the development of superbugs like methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, and metallo-beta-lactamase producing Pseudomonas aeruginosa. Regular monitoring of antimicrobial resistance and maintaining hygiene, especially in hospitalized patients are required to control biofilm-related infections in order to prevent antimicrobial resistance.202236705135
884820.9995Harnessing the effect of iron deprivation to attenuate the growth of opportunistic pathogen Acinetobacter baumannii. Acinetobacter baumannii is an opportunistic pathogen having high infectivity among immunocompromised patients. The bacteria are resistant to major first-line antibiotics and have become a serious concern in the aspect of nosocomial and community-acquired infections. To overcome this dire situation, the necessity of introducing new approaches is undeniable, which can bypass the need for conventional antibiotic therapy. In this article, we have pinpointed the importance of iron in A. baumannii. Iron is an essential micronutrient in all bacteria. Loss of iron acquisition leads to membrane destabilization, and change in the expression of iron-transporting or -metabolizing genes causes death of the bacteria. Iron scavenging was primarily mediated by different chelators, and β-thujaplicin showed the best antibacterial efficacy with respect to time killing assay and CFU analysis. When iron (Fe(2+)) was supplemented after initial deficiency, the growth of the bacteria was seen to be restored. Iron deprivation also disintegrates the biofilm matrix, a major cause of bacterial resistance against different types of antibiotics. Moreover, iron scavenging promotes inhibition of biofilm sessile persister cells, the root cause of recalcitrant and chronic infection. As a part of antimicrobial therapy, β-thujaplicin was treated alongside colistin and chloramphenicol at an amount significantly lower than its MIC value. Our results indicated that β-thujaplicin nicely complemented those antibiotics to potentiate their antimicrobial action. In a nutshell, iron chelating agents are potential alternative therapeutics that can be used alongside different antibiotics to circumvent the resistance of different nosocomial pathogens.202540202344
883930.9995Bacteriophage infection drives loss of β-lactam resistance in methicillin-resistant Staphylococcus aureus. Bacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here, we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence are downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.202540637714
978740.9995CRISPR-Cas, a Revolution in the Treatment and Study of ESKAPE Infections: Pre-Clinical Studies. One of the biggest threats we face globally is the emergence of antimicrobial-resistant (AMR) bacteria, which runs in parallel with the lack in the development of new antimicrobials. Among these AMR bacteria pathogens belonging to the ESKAPE group can be highlighted (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) due to their profile of drug resistance and virulence. Therefore, innovative lines of treatment must be developed for these bacteria. In this review, we summarize the different strategies for the treatment and study of molecular mechanisms of AMR in the ESKAPE pathogens based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins' technologies: loss of plasmid or cellular viability, random mutation or gene deletion as well directed mutations that lead to a gene's loss of function.202134206474
476950.9994Human breast milk isolated lactic acid bacteria: antimicrobial and immunomodulatory activity on the Galleria mellonella burn wound model. INTRODUCTION: Managing burn injuries is a challenge in healthcare. Due to the alarming increase in antibiotic resistance, new prophylactic and therapeutic strategies are being sought. This study aimed to evaluate the potential of live Lactic Acid Bacteria for managing burn infections, using Galleria mellonella larvae as an alternative preclinical animal model and comparing the outcomes with a common antibiotic. METHODS: The antimicrobial activity of LAB isolated from human breast milk was assessed in vitro against Pseudomonas aeruginosa ATCC 27853. Additionally, the immunomodulatory effects of LAB were evaluated in vivo using the G. mellonella burn wound infection model. RESULTS AND DISCUSSION: In vitro results demonstrated the antimicrobial activity of Lactic Acid Bacteria against P. aeruginosa. In vivo results show that their prophylactic treatment improves, statistically significant, larval survival and modulates the expression of immunity-related genes, Gallerimycin and Relish/NF-κB, strain-dependently. These findings lay the foundation and suggest a promising alternative for burn wound prevention and management, reducing the risk of antibiotic resistance, enhancing immune modulation, and validating the potential G. mellonella as a skin burn wound model.202439310784
425260.9994Extreme antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance.201122919572
425170.9994Extreme antimicrobial Peptide and polymyxin B resistance in the genus burkholderia. Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance.201121811491
975780.9994Effects of different mechanisms on antimicrobial resistance in Pseudomonas aeruginosa: a strategic system for evaluating antibiotics against gram-negative bacteria. Our previous studies constructed a strategic system for testing antibiotics against specific resistance mechanisms using Klebsiella pneumoniae and Acinetobacter baumannii. However, it lacked resistance mechanisms specifically expressed only in Pseudomonas species. In this study, we constructed this system using Pseudomonas aeruginosa. In-frame deletion, site-directed mutagenesis, and plasmid transformation were used to generate genetically engineered strains with various resistance mechanisms from two fully susceptible P. aeruginosa strains. Antimicrobial susceptibility testing was used to test the efficacy of antibiotics against these strains in vitro. A total of 31 engineered strains with various antimicrobial resistance mechanisms from P. aeruginosa KPA888 and ATCC 27853 were constructed, and the same antibiotic resistance mechanism showed a similar effect on the MICs of the two strains. Compared to the parental strains, the engineered strains lacking porin OprD or lacking the regulator genes of efflux pumps all showed a ≥4-fold increase on the MICs of some of the 19 antibiotics tested. Mechanisms due to GyrA/ParC mutations and β-lactamases also contributed to their corresponding resistance as previously published. The strains constructed in this study possess well-defined resistance mechanisms and can be used to screen and evaluate the effectiveness of antibiotics against specific resistance mechanisms in P. aeruginosa. Building upon our previous studies on K. pneumoniae and A. baumannii, this strategic system, including a P. aeruginosa panel, has been expanded to cover almost all the important antibiotic resistance mechanisms of gram-negative bacteria that are in urgent need of new antibiotics.IMPORTANCEIn this study, an antibiotic assessment system for P. aeruginosa was developed, and the system can be expanded to include other key pathogens and resistance mechanisms. This system offers several benefits: (i) compound design: aid in the development of compounds that can bypass or counteract resistance mechanisms, leading to more effective treatments against specific resistant strains; (ii) combination therapies: facilitate the exploration of combination therapies, where multiple antibiotics may work synergistically to overcome resistance and enhance treatment efficacy; and (iii) targeted treatments: enable healthcare providers to prescribe more targeted treatments, reducing unnecessary antibiotic use and helping to slow the spread of antibiotic resistance. In summary, this system could streamline the development process, reduce costs, increase the success rate of new antibiotics, and help prevent and control antimicrobial resistance.202540042282
975590.9994Phages for treatment Pseudomonas aeruginosa infection. Pseudomonas aeruginosa is denoted as one of the highly threatening bacteria to the public health. It has acquired many virulent factors and resistant genes that make it difficult to control with conventional antibiotics. Thus, bacteriophage therapy (phage therapy) is a proposed alternative to antibiotics to fight against multidrug-resistant P. aeruginosa. Many phages have been isolated that exhibit a broad spectrum of activity against P. aeruginosa. In this chapter, the common virulent factors and the prevalence of antibiotic-resistance genes in P. aeruginosa were reported. In addition, recent efforts in the field of phage therapy against P. aeruginosa were highlighted, including wild-type phages, genetically modified phages, phage cocktails, and phage in combination with antibiotics against P. aeruginosa in the planktonic and biofilm forms. Recent regulations on phage therapy were also covered in this chapter.202337770166
9400100.9994Conjugative Delivery of CRISPR-Cas9 for the Selective Depletion of Antibiotic-Resistant Enterococci. The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) that are recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiont Enterococcus faecalis is associated with HAIs, and some strains are MDR. Therefore, novel strategies to control E. faecalis populations are needed. We previously characterized an E. faecalis type II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here, we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers to E. faecalis for the selective removal of antibiotic resistance genes. Using in vitro competition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistant E. faecalis by several orders of magnitude. Finally, we show that E. faecalis donor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinants in vivo Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.201931527030
8849110.9994Attenuating the Selection of Vancomycin Resistance Among Enterococci through the Development of Peptide-Based Vancomycin Antagonists. The emergence and spread of multidrug resistant (MDR) pathogens with acquired resistance to almost all available antimicrobial agents has severely threatened the international healthcare community over the last two decades. The last resort antibiotic vancomycin is critical for treatment of several of these pathogens; howeverc vancomycin resistance is spreading due to the undesired accumulation of IV vancomycin in the colon post-treatment. This accumulation exerts selective pressure upon members of the colonic microflora, including Enterococci, which possess vancomycin resistance genes. To ensure the continual effectiveness of vancomycin in the clinical setting by preventing the spread of antibiotic resistance, it is crucial to develop strategies that reduce selective pressure on the colonic microflora while allowing vancomycin to maintain its desired activity at the site of infection. Herein we report that modification of the native l-Lys-d-Ala-d-Ala vancomycin binding site can be used to produce peptides with the ability to competitively bind vancomycin, reducing its activity against susceptible Enterococci. Moreover, several modifications to the N-termini of the native tripeptide have produced compounds with enhanced vancomycin binding activity, including several analogs that were designed to covalently bind vancomycin, thereby acting as suicide inhibitors. Finally, in a mixed culture of susceptible and resistant bacteria, a single lead compound was found to protect high ratios of susceptible bacteria from vancomycin over the course of a week-long period, preventing the selection for vancomycin-resistant Enterococci. These findings demonstrate the ability of these peptides as potential therapeutic adjuvants for counteracting the undesired accumulation of colonic vancomycin, allowing for protection of the colonic microflora.202032946213
9767120.9994Metallo-β-lactamase NDM-1 serves as a universal vaccine candidate for combatting antimicrobial resistance. The rapid emergence and spread of antimicrobial resistance have become critical global health issues, leading to significant morbidity and mortality worldwide. With the increase in resistance to multiple drugs, especially frontline clinical antibiotics, there is an urgent need for novel and effective alternative strategies. Herein, we developed a vaccine targeting the antimicrobial resistance enzyme NDM-1, which was first identified in Klebsiella pneumoniae and has quickly spread to other gram-negative bacteria. Our results demonstrate that NDM-1 primarily triggers a humoral immune response and effectively protects mice from lethal Klebsiella pneumoniae infection, as evidenced by increased survival rates, reduced bacterial loads, and decreased lung inflammation in mice. The specific antibodies generated were able to inhibit the enzymatic activity of NDM-1, bacterial growth, and exhibit opsonophagocytic activity against Klebsiella pneumoniae in vitro. Both active and passive immunization with NDM-1 showed an additive effect when combined with meropenem therapy. Furthermore, NDM-1 immunization induced cross-reactivity with NDM-1 variants, potentially providing broad protection against bacteria carrying different NDM genes. Additionally, heptamerization of NDM-1 improved its immunogenicity and protective efficacy in mice. These results highlight the potential of vaccine development based on antibiotic resistance candidates for broadly combatting antimicrobial resistance.202540505900
4386130.9994Large-scale screening of a targeted Enterococcus faecalis mutant library identifies envelope fitness factors. Spread of antibiotic resistance among bacteria responsible for nosocomial and community-acquired infections urges for novel therapeutic or prophylactic targets and for innovative pathogen-specific antibacterial compounds. Major challenges are posed by opportunistic pathogens belonging to the low GC% gram-positive bacteria. Among those, Enterococcus faecalis is a leading cause of hospital-acquired infections associated with life-threatening issues and increased hospital costs. To better understand the molecular properties of enterococci that may be required for virulence, and that may explain the emergence of these bacteria in nosocomial infections, we performed the first large-scale functional analysis of E. faecalis V583, the first vancomycin-resistant isolate from a human bloodstream infection. E. faecalis V583 is within the high-risk clonal complex 2 group, which comprises mostly isolates derived from hospital infections worldwide. We conducted broad-range screenings of candidate genes likely involved in host adaptation (e.g., colonization and/or virulence). For this purpose, a library was constructed of targeted insertion mutations in 177 genes encoding putative surface or stress-response factors. Individual mutants were subsequently tested for their i) resistance to oxidative stress, ii) antibiotic resistance, iii) resistance to opsonophagocytosis, iv) adherence to the human colon carcinoma Caco-2 epithelial cells and v) virulence in a surrogate insect model. Our results identified a number of factors that are involved in the interaction between enterococci and their host environments. Their predicted functions highlight the importance of cell envelope glycopolymers in E. faecalis host adaptation. This study provides a valuable genetic database for understanding the steps leading E. faecalis to opportunistic virulence.201122194979
9791140.9994Beta-lactam resistance and the effectiveness of antimicrobial peptides against KPC-producing bacteria. Bacterial resistance is a problem that is giving serious cause for concern because bacterial strains such as Acinetobacter baumannii and Pseudomonas aeruginosa are difficult to treat and highly opportunistic. These bacteria easily acquire resistance genes even from other species, which confers greater persistence and tolerance towards conventional antibiotics. These bacteria have the highest death rate in hospitalized intensive care patients, so strong measures must be taken. In this review, we focus on the use of antimicrobial peptides (AMPs) as an alternative to traditional drugs, due to their rapid action and lower risk of generating resistance by microorganisms. We also present an overview of beta-lactams and explicitly explain the activity of AMPs against carbapenemase-producing bacteria as potential alternative agents for infection control.202236042694
9804150.9994Antimicrobial Peptides as an Alternative for the Eradication of Bacterial Biofilms of Multi-Drug Resistant Bacteria. Bacterial resistance is an emergency public health problem worldwide, compounded by the ability of bacteria to form biofilms, mainly in seriously ill hospitalized patients. The World Health Organization has published a list of priority bacteria that should be studied and, in turn, has encouraged the development of new drugs. Herein, we explain the importance of studying new molecules such as antimicrobial peptides (AMPs) with potential against multi-drug resistant (MDR) and extensively drug-resistant (XDR) bacteria and focus on the inhibition of biofilm formation. This review describes the main causes of antimicrobial resistance and biofilm formation, as well as the main and potential AMP applications against these bacteria. Our results suggest that the new biomacromolecules to be discovered and studied should focus on this group of dangerous and highly infectious bacteria. Alternative molecules such as AMPs could contribute to eradicating biofilm proliferation by MDR/XDR bacteria; this is a challenging undertaking with promising prospects.202235336016
9792160.9994Emergence of antibiotic resistance Pseudomonas aeruginosa in intensive care unit; a critical review. The emergence of antibiotic resistant bacteria in the healthcare is a serious concern. In the Healthcare premises precisely intensive care unit are major sources of microbial diversity. Recent findings have demonstrated not only microbial diversity but also drug resistant microbes largely habitat in ICU. Pseudomonas aeruginosa found as a part of normal intestinal flora and a significant pathogen responsible for wide range of ICU acquired infection in critically ill patients. Nosocomial infection associated with this organism including gastrointestinal infection, urinary tract infections and blood stream infection. Infection caused by this organism are difficult to treat because of the presence of its innate resistance to many antibiotics (β-lactam and penem group of antibiotics), and its ability to acquire further resistance mechanism to multiple class of antibiotics, including Beta-lactams, aminoglycosides and fluoroquinolones. In the molecular evolution microbes adopted several mechanism to maintain genomic plasticity. The tool microbe use for its survival is mainly biofilm formation, quorum sensing, and horizontal gene transfer and enzyme promiscuity. Such genomic plasticity provide an ideal habitat to grow and survive in hearse environment mainly antibiotics pressure. This review focus on infection caused by Pseudomonas aeruginosa, its mechanisms of resistance and available treatment options. The present study provides a systemic review on major source of Pseudomonas aeruginosa in ICU. Further, study also emphasizes virulence gene/s associated with Pseudomonas aeruginosa genome for extended drug resistance. Study gives detailed overview of antibiotic drug resistance mechanism.201931194018
4308170.9994Interplay between ESKAPE Pathogens and Immunity in Skin Infections: An Overview of the Major Determinants of Virulence and Antibiotic Resistance. The skin is the largest organ in the human body, acting as a physical and immunological barrier against pathogenic microorganisms. The cutaneous lesions constitute a gateway for microbial contamination that can lead to chronic wounds and other invasive infections. Chronic wounds are considered as serious public health problems due the related social, psychological and economic consequences. The group of bacteria known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp.) are among the most prevalent bacteria in cutaneous infections. These pathogens have a high level of incidence in hospital environments and several strains present phenotypes of multidrug resistance. In this review, we discuss some important aspects of skin immunology and the involvement of ESKAPE in wound infections. First, we introduce some fundamental aspects of skin physiology and immunology related to cutaneous infections. Following this, the major virulence factors involved in colonization and tissue damage are highlighted, as well as the most frequently detected antimicrobial resistance genes. ESKAPE pathogens express several virulence determinants that overcome the skin's physical and immunological barriers, enabling them to cause severe wound infections. The high ability these bacteria to acquire resistance is alarming, particularly in the hospital settings where immunocompromised individuals are exposed to these pathogens. Knowledge about the virulence and resistance markers of these species is important in order to develop new strategies to detect and treat their associated infections.202133540588
8918180.9994Antibiotic resistance alters the ability of Pseudomonas aeruginosa to invade bacteria from the respiratory microbiome. The emergence and spread of antibiotic resistance in bacterial pathogens is a global health threat. One important unanswered question is how antibiotic resistance influences the ability of a pathogen to invade the host-associated microbiome. Here we investigate how antibiotic resistance impacts the ability of a bacterial pathogen to invade bacteria from the microbiome, using the opportunistic bacterial pathogen Pseudomonas aeruginosa and the respiratory microbiome as our model system. We measure the ability of P. aeruginosa spontaneous antibiotic-resistant mutants to invade pre-established cultures of commensal respiratory microbes in an assay that allows us to link specific resistance mutations with changes in invasion ability. While commensal respiratory microbes tend to provide some degree of resistance to P. aeruginosa invasion, antibiotic resistance is a double-edged sword that can either help or hinder the ability of P. aeruginosa to invade. The directionality of this help or hindrance depends on both P. aeruginosa genotype and respiratory microbe identity. Specific resistance mutations in genes involved in multidrug efflux pump regulation are shown to facilitate the invasion of P. aeruginosa into Staphylococcus lugdunensis, yet impair invasion into Rothia mucilaginosa and Staphylococcus epidermidis. Streptococcus species provide the strongest resistance to P. aeruginosa invasion, and this is maintained regardless of antibiotic resistance genotype. Our study demonstrates how the cost of mutations that provide enhanced antibiotic resistance in P. aeruginosa can crucially depend on community context. We suggest that attempts to manipulate the microbiome should focus on promoting the growth of commensals that can increase the fitness costs associated with antibiotic resistance and provide robust inhibition of both wildtype and antibiotic-resistant pathogen strains.202439328287
8850190.9994Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides. Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.201829795541